Inherited bone marrow failure syndromes ASH education 2020

 Fanconi Anemia

Diamond Blackfan

Short telomere syndrome

Fanconi Anemia

1. Use radiation-free RIC conditioning regimens

2. Bone marrow T replete is the preferred source, since peripheral blood is associated with higher risk of malignancies and GVHD

3.  Fanconi anemia- confirm with DEB test. HCT in indicated before MDS, AML and transfusion dependence. Low-dose cyclophosphamide (CY) 20 to 40 mg/kg and fludarabine with or without antithymocyte globulin (ATG) is the most common regimen. OS over 90%. 

4. Androgens in the aplastic phase while awaiting HCT can lead to response in 80% of patients.

5.  What to counsel and monitor when giving androgens: does not prevent clonal evolution. Need to monitor for LFT abn, liver adenomas, lipid issues and virilization in young girls. Donor may not be available later.

6. HCT after MDS or AML leads to lower survival. Less than 50% at 5 yr

7. FA patients continue to be at risk for developing cancer after transplant, especially head and neck SCC, and the use irradiation-containing regimens and/or GVHD may increase the incidence of this complication. Lifelong aggressive surveillance for early detection of cancer is recommended because the treatment options in FA are limited

Telemore biology disorder-- Dyskeratosis congenita 

1. TINF2 mutation

2. Dyskeratosis congenita (DC) represents the prototype of TBD and is characterized by bone marrow failure and the classical triad of reticular skin pigmentation, oral leukoplakia, and nail dystrophy.

3. Pulm AV malformations, GI telangiectasia common. Can develop hepatopulmonary shunts.

4. 10 yr survival after HCT only 30%.

Diamond Blackfan

1. Defective ribogenesis

2. standard of care for DBA includes corticosteroids and chronic transfusions with adequate iron chelation

3. Chelation when patient has received 200 ml/kg bwt of transfusion.

4. HCT is the only curative option for the hematologic manifestations of DBA and is recommended for patients who fail to respond to corticosteroids and/or need chronic transfusion. We and others consider treatment failure as needing corticosteroids (dose >0.3 mg/kg per day) to maintain hemoglobin >8 g/dL.

5. Screen potential donors for silent DBA trait. Test- elevated erythrocyte deaminase

Others:

Shwachman-Diamond syndrome is a recessive disorder characterized by bone marrow failure, exocrine pancreatic insufficiency, and skeletal abnormalities. Malignant transformation is frequent, ranging between 5% and 25%. The indications for transplant are worsening cytopenias and transformation into MDS and AML